Table 1. Potential AD projects.

Proposed projects for an AD megafund portfolio and the estimated “degree of validation” for each. Uppercase entries indicate hypotheses, boldface entries indicate categories, and remaining entries indicate projects. In cases in which hypotheses and categories are more speculative, they may constitute single projects. Entries containing numbers in parentheses indicate multiple projects.

ProjectsDegree of validation
AMYLOID
Aβ passive immunotherapy
Aβ antibodies (6)High
Pyro Aβ antibodies (3)High
Antibodies against soluble oligomers (3)High
Aβ synthesis
β-secretase inhibitors (6)Medium
γ-secretase inhibitors and modulators (3)Low
α-secretase agonismLow
Aβ antiaggregation inhibitors/beta-sheet breakersLow
Aβ clearance
Neprilsyn and plasminLow
Insulin-degrading enzymeLow
Low-density lipoprotein receptor overexpressionLow
TAU PATHWAY
Phosphorlyation inhibitors
CDK5Low
GSK3βLow
MARK/par1Low
PKCLow
MAPKLow
PKALow
p70S6KLow
Antiaggregants (TRx0237) Low
Microtubule stabilizing agents (BMS 241027) Low
Reduction of tau levels (Tau antibodies and antisense oligonucleotides) Low
APOE4/LIPID METABOLISM
Activated receptor gamma and liver X receptors in coordination with RXR’sLow
SIRT1, sirtuinLow
GIVA-PLA2Low
NEUROINFLAMMATION
Complement receptor 1Low
TREM 2Low
PPAR agonistsLow
IL-1, IL-6, IL-12, IL-23Low
TNFRLow
P2X7RLow
Monoacylglycerol lipaseLow
AUTOPHAGY/PROTEASOME/UNFOLDED PROTEIN RESPONSE
NilotinibLow
Proteasome pathwaysLow
Unfolded protein responseLow
HORMONES/GROWTH FACTORS
Inactivation of gonadotropin-releasing hormone (GnRH)Low
AllopregnanoloneLow
CERE-110: Adeno-associated virus delivery of nerve growth factorLow
DYSREGULATION OF CALCIUM HOMEOSTASIS
InsP3RLow
CALHM1Low
HEAVY METALS
CopperLow
ZincLow
MITOCHONDRIAL CASCADE/MITOCHONDRIAL UNCOUPLING/ANTIOXIDANTS (3)Low
DISEASE-RISK GENES (3)Low
HDAC INHIBITORSLow
GLUCOSE METABOLISMLow